rs17003235

chr4-78450320-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):c.6444C>T(p.Thr2148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,613,304 control chromosomes in the GnomAD database, including 37,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34198 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.561

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-78450320-C-T is Benign according to our data. Variant chr4-78450320-C-T is described in ClinVar as [Benign]. Clinvar id is 261809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-78450320-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.561 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRAS1	NM_025074.7	c.6444C>T	p.Thr2148=	synonymous_variant	45/74	ENST00000512123.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRAS1	ENST00000512123.4	c.6444C>T	p.Thr2148=	synonymous_variant	45/74	5	NM_025074.7	P1
FRAS1	ENST00000682513.1	c.6444C>T	p.Thr2148=	synonymous_variant	45/64
FRAS1	ENST00000684159.1	c.6444C>T	p.Thr2148=	synonymous_variant	45/45

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31858 AN: 151920 Hom.: 3653 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.163 AC: 40697 AN: 249132 Hom.: 4181 AF XY: 0.160 AC XY: 21681 AN XY: 135160

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.00172

Gnomad SAS exome AF: 0.0713

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.207 AC: 302420 AN: 1461266 Hom.: 34198 Cov.: 33 AF XY: 0.202 AC XY: 146852 AN XY: 726948

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.117

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.0738

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.210 AC: 31872 AN: 152038 Hom.: 3651 Cov.: 32 AF XY: 0.202 AC XY: 15024 AN XY: 74310

Gnomad4 AFR AF: 0.277

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0654

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.193

Alfa AF: 0.216 Hom.: 1973

Bravo AF: 0.212

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.211

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Fraser syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	2.0
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17003235; hg19: chr4-79371474;